This invention relates to a novel class of substituted azoles and, more specifically, diaryl substituted thiazoles, diaryl substituted thiadiazoles and diaryl substituted oxadiazoles, compounds which are useful in the treatment of fungal infections in mammals including humans. These compounds are active against a broad spectrum of fungi such as Candida albicans, Candida parpsilosis, Candida tropicalis, Candida Krusei, Cryptococcus neoformans, Aspergillus fumigatus and Torulopsis glabrata. Moreover, compounds within this series are also active against Fluconazole resistant strains and isolates.
Opportunistic fungal infections are responsible for increased morbidity and mortality among patients suffering from AIDS and other immunocompromised diseases including infections resulting from neutropenia, cancer chemotherapy and organ transplantation (Annals N.Y. Acad. Sc., 544:1-3).
Moreover, until recently, the treatment of deep seated fungal infections has lagged behind the treatment of bacterial infections and only a few systemic agents are available for combatting these invasive pathogens.
Current therapy provides for administering polyenes such as amphotericin B, allylamines such as Naftafin and Terbinafin and azoles such as Fluconazole, Itraconazole and Ketoconazole. Amphotericin B, once the treatment of choice, is no longer favored due to the acute and chronic toxicities associated with its use.
Also, antifungal azoles are fungistatic, not fungicidal, and this has resulted in azole resistant fungi, that is, fungi strains and isolates which are resistant to treatment with Fluconazole and other known antifungal agents (New Engl. J. Med., 1944, 330: 263-272.)
Azole compounds in which hydroxy and/or carboxy groups comprise the molecular structure are known to be useful in combatting pathogenic fungi,
For example, British Patent No. 2,099,818 and U.S. Pat. No. 4,404,216 disclose Fluconazole 
a triazole derivative which has played an important role in protecting against a variety of fungi.
Also, DE-4124942 discloses azoles of the following structure having antithrombotic and fibrinogen-binding activities: 
wherein: one of X1-X5=Q1-Q3, a second=Q4-Q6, a third=S, SO, N, R1N, R2C, (R2)2C, a fourth=O, S, N, SO2, R2C, CO, and a fifth=R2C, (R2)2C, N; A=cyano, (substituted) phenylene, pyridinylene, pyrazinylene, triazinylene, C=(substituted) phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, triazinylene, cycloalkylene) cycloalkylene; D=(substituted) alkylene, alkeylene, etc.; E=bond, alkylene, etc., F=carboxy, (substituted) alkoxycarbonyl; R1=H, alkyl, aralkyl, aryl, heteroaryl; R=H, Cl, Br, alkyl, aralkyl, aryl, heteroaryl, alkoxy, R1O2C, (R1)2N, etc. These compounds are said to have antithrombotic and fibrinogen-binding activity. The closest example is 4-(4-amidinophenyl)-2-[4-(2-carboxyethyl)phenyl]thiazole. 
WO-9209586 (FP 0 513387 A1) discloses thiazole derivatives represented by the following structure useful as superoxide radical inhibitors: 
wherein:
R1 is substituted phenyl, pyridyl, thienyl, carbostyril, pyrazyl, pyrrolyl, quinolyl, 3,4-dihydrocarbostyril;
R2 is hydrogen, halo, alkyl, phenyl, alkoxycarbonyl, alkylamino, and the like;
X is sulfur or oxygen;
R3 is Q (supra) wherein R is hydroxyl, carboxylic acid, alkyl, alkenyl and m is 0-2 or, R3 may be T (supra), wherein R4 is hydrogen or alkyl and R is aminoalkyl.
The structure activity relationship (SAR) of the above series has been published in the J. Med. Chem. 1995, 38, 353-358 where the following general structure is shown: 
WO-9324472 (EP 0 600092 A1) discloses compounds of the following structure as an active oxygen inhibitor: 
wherein:
R1 is Ph which may be substituted by 1 to 3 alkoxy groups; and
R2 is a substituted pyridylcarbonyl which may be substituted by alkoxycarbonyl, carboxyl, a 5 to 15 membered mono-, di-, or tricyclic heterocyclic ring residue having 1 to 3 N, O or S, atoms, or a phenylmoiety of the formula. 
wherein, R3 represents carboxyl, lower alkoxycarbonyl, hydroxyl substituted lower alkyl, lower alkoxy, tri-lower alkyl-substituted silyloxy, hydroxy, or hydrogen; R4 represents hydrogen, lower alkenyl or lower alkyl; R5 represents an amino-lower alkoxycarbonyl which may be substituted further by lower alkyl, amino-lower alkoxy, or lower alkoxy or the like.
U.S. Pat. No. 4,791,200 describes compounds of the following structure useful as antisecretory agents: 
wherein:
R is C1 to C4 alkyl, phenyl, phenyl substituted by CF1, halo selected from I, Br or Cl, C1-C3 alkyl, alkoxy, acetamido, nitro, cyano, alkyamino or dialkylamino having 1-4 carbons or pyridyl;
R1 is H or C1-C4 alkyl,
R2 is H, C1-C4 alkyl, C1-C3 alkoxy or, Cl Br or I,
R3 or R4 are xe2x80x94Oxe2x80x94(CH2)mxe2x80x94NR5R6 wherein m=1-3.
Patel and Colah in Bull Haff Instt. (1977), 5, 72-74 disclose p-(2-substituted-4-thiazoly)phenylacetic acid and p-(2-substituted-4-thiazolyl)phenoxyacetic acids useful in treating tuberculosis and fungi: 
wherein R1 is CH2COOH or OCH2COOH; and
Ar is phenyl, substituted phenyl or benzyl and the like.
Kirke et al in Bull. Haffkine Inst., (1977), 5, 75-7, and (1974), 2, 28-31 disclose a series of thiazolyl phenoxyacetic acids and derivatives having in vitro antituberculosis and antifungal activity against T. rubrum and T. mentagrophytes, 
Anne et al in Antimicrob. Agents Chemother., (1980), 18(2), 231-9 disclose diaryloxadiazole derivatives having only very weak activity against Candida albican (MIC50 greater than 60 xcexcg/ml) as, for example: 
This invention relates to diaryl substituted azoles and pharmaceutically acceptable salts thereof useful as antifungal agents.
This invention also includes methods for preparing said azoles and antifungal compositions containing these compounds or a pharmaceutically acceptable salt thereof as the active ingredient.
The azoles of this invention are compounds of the general formula: 
wherein:
Ar is phenyl, thienyl, pyridyl substituted with R1R2 where R1, R2 are independently hydrogen or halogen such as F, Cl, Br and I; alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxyl, cyano, nitro, COCH, aminocarbonyl or aminosulfonyl, alkylamino, diakylamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl, alkylamino, dialkylamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl or, taken together, R1, R2 may form a ring xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94 wherein n=1,2;
R3, R4 are independently hydrogen, C1-C16 alkyl which may optionally be substituted with amino, dialkylamino, hydroxy, cyano, carboxy; alkenyl, alkynyl, acyl or, taken together, R3 and R4 may be xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)mxe2x80x2xe2x80x94 where mxe2x80x2=m=2, Q=CH2,O, S(O)n, n=0-2, NR7 wherein R7 is C1-C3 alkyl with the proviso that when Q is CH2, mxe2x80x2 can also be 1;
R5 is H, halogen as defined above, OR, OH, NO2, NH2 or NHCOR where R is lower alkyl, alkyl or aryl, and the like.
X is N, O or S;
Y is N or S, with the proviso when X=O or S, Y must be N;
Z is N or CR8, where R8 is hydrogen, halogen such as Cl, Br or I, lower alkyl or alkoxycarbonyl, with the proviso that X, Y and Z cannot all be N at the same time.
V is N, O or S, and when V is N, it may also be combined with R3 and R4 to form a heterocycle such as pyrrole, imidazol-1,2,4,-triazole, 1,3,4-triazole and pyrazole, and when V is O or S, R3 and R4 combine to form a single substituent having the definition of R4 alone; and
P is an integer having a value of 1-3.
Specifically, this invention relates to thiazoles of the formula: 
wherein: R1, R2, R3, R4, R5, p and V are each as defined above in formula (I) and R6 is hydrogen, halogen, carboxy, alkoxy carbonyl, lower alkyl, hydroxy and lower alkoxy and the nontoxic pharmacologically acceptable salts thereof.
This invention also relates to thiadiazoles of the following formula: 
wherein: R1, R2, R3, R4, R5, p and V are each as defined above in formula (I), and the nontoxic pharmaceutically acceptable salts thereof.
This invention also relates to thiadiazoles of the formula: 
wherein: R1, R2, R3, R4, R5, p and V are as defined above in formula (I), and the nontoxic pharmaceutically acceptable salts thereof.
This invention also relates to oxadiazoles of the formula: 
wherein: R1, R2, R3, R4, R5, p and V are as defined above in formula (I), and the nontoxic pharmaceutically acceptable salts thereof.
More specifically, this invention relates to thiazoles of the formula: 
wherein: R1, R2, R3, R4, are as defined above in formula (I), and the nontoxic pharmaceutically acceptable salts thereof.
This invention also relate to diazoles of the formula: 
wherein: R1, R2, R3, R4 are as defined above and X is O or S, and pharmaceutically acceptable salts thereof.
Alternatively and according to another embodiment, the preferred products of this invention are those represented by the formulae identified as VIII-XIII hereinbelow.
In general, the preferred products are those which conform to formula VIII and formula IX: 
wherein:
AR is selected from among pyridyl, halo substituted pyridyl and 
xe2x80x83where R8 is hydrogen, halo, nitro, amino, triflouromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl and trimethylsilyl lower alkynyl; and R9 is hydrogen, nitro, lower alkoxy or cyano;
X is S or O;
Y is CH or N;
Z is CH or N;
B is lower alkylene or lower alkynylene;
D is SR10, OR11 or N(R12R13) wherein R10 is di-lower alkylaminoalkyl; R11 is di-lower alkylaminoalkyl, lower alkenyl, lower alkynyl or lower alkoxyakyl; R12 and R13 are the same or different and represent hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower cycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl, di-lower alkylaminoalkylcarbonyl or, taken together, R12 and R13 may be combined to form xe2x80x94CH2CH2N(R14)CH2CH2xe2x80x94 or xe2x80x94CH2CH2SCH2CH2xe2x80x94 where R14 represents lower alkyl; and
R15 is hydrogen, nitro, amino, lower alkanamido or hydroxy; and the nontoxic pharmacologically acceptable salts thereof.
Another preferred embodiment are the thiazole compounds represented by formula X: 
wherein:
R8 is hydrogen, halo, nitro, amino, triflouromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl, trimethylsilyl lower alkynyl; and R9 is hydrogen, nitro, lower alkoxy or cyano;
R12 and R13 are the same or different and represent hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower cycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl, di-lower alkylaminoalkylcarbonyl or, taken together, R12 and R13 may be combined to form xe2x80x94CH2CH2N(R14)CH2CH2xe2x80x94 or xe2x80x94CH2CH2SCH2CH2xe2x80x94 wherein R14 represents lower alkyl;
R15 is hydrogen, nitro, amino, lower alkanamido or hydroxy; and
n is an integer having a value of 1 to 3, and the nontoxic pharmacologically acceptable salts thereof.
Still another preferred embodiment are thiazoles of the following formula: 
wherein:
R16 is hydrogen, halo, nitro, lower alkoxy, cyano, trifluoromethyl or lower alkyl;
R17 is hydrogen, nitro, halogen or cyano;
R18 and R19 are the same or different and represent hydrogen, lower alkyl, lower alkenyl, di-lower alkylaminoalkyl, hydroxy lower alkyl and lower alkylaminoalkyl; and
R20 is hydrogen or hydroxy, and the nontoxic pharmacologically acceptable salts thereof.
Another preferred embodiment provides for diazoles having the formula: 
wherein:
R21 is selected from among hydrogen and lower alkoxy;
R22 is selected from among hydrogen and nitro; and
R23 and R24 are lower alkyl, and the nontoxic pharmacologically acceptable salts thereof.
Also included among the preferred embodiments are thiadiazoles of formula XIII: 
wherein:
E is SR26 or NR27R28 wherein R26 is di-lower alkylaminoalkyl R27 and R28 are the same or different and represent lower alkyl and lower alkenyl, and the nontoxic pharmacologically acceptable salts thereof.
The aforecited compounds are useful in the treatment of broad spectrum fungal infections, and they are also active against a variety of fungi and fungal isolates including Fluconazole-resistant isolates and strains. These compounds are useful for this purpose when used in the concentration range of 250 xcexcg/ml and below.
Appropriate compounds of formula I to XIII are useful in the free base form, in the form of base salts where possible, and in the form of acid addition salts. In practice, use of the salt form is equivalent to use of the base form.
Pharmaceutically acceptable salts within the scope of this invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid and the like including organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. These afford the corresponding hydrochloride, sulfate, ethanesulfonate, benzenesulfonate, p-hydrochloride and the like, respectively; however, this invention is not limited to those mentioned above since equivalent salts will be apparent to those skilled in this art.
Examples of pharmaceutically acceptable base addition salts include organic bases which are nontoxic and of such strength as to form usable salts. These organic bases form a class whose limits are readily understood by those skilled in the art, and for the purposes of illustration, they include mono-, di, and trialkylamines such as methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-, or triethanolamine, amino acids such as arginine and lysine; guanidine; N-methyl-glucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like. (See, for example, xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 66(1):1-19 (1977).) Salts of inorganic bases include sodium, potassium, calcium or the like.
The acid addition salts of said basic compounds are prepared either by dissolving the free base of compound I to XIII in aqueous or aqueous alcohol solution of other suitable solvents containing appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base of compound I to XIII, having an acid group thereon with a base such that the reactions are in an organic solvent, in which case, the salt separates directly or can be obtained by concentration of the solution. Salts can also be prepared by adding base to an aqueous alcohol solution of another salt.
Generally, the compounds of formulas (I) to (XIII) can be prepared by the processes identified as 1-9 hereinbelow: Process 1 (Scheme 1): 
In this process (Scheme 1), the substituted thiobenzamide (2) is prepared according to the literature procedure (Tetrahedron, 41, (22), 5061, 1985, M. Cava and M. Levinson) by refluxing benzamide (1) with Lawesson""s reagent in dry benzene or toluene (M. Levinson). A condensation reaction between the thiobenzamide and xcex1-haloacetophenone derivatives in solvent such as low alcohol, THF, CH1CN, etc., gives 2,4-diarylthiazole compounds (3) (Organic Synthesis, Coll. III, 332). The NBS bromination of the compound (3) affords the bromomethyl products (4a) and/or (4b), which are converted to compounds (5) and (6) respectively by reacting with appropriate nucleophile as shown in Scheme 1. Compound (5) can also be de-brominated by catalytic hydrogenation to give compound (6).
Process 2 (Scheme 2): 
An alternative synthetic pathway is illustrated in Scheme 2, which involves the bromination of ethyl 4-acetylbenzoate with bromine in ether in the presence of catalytic amount of aluminum chloride. The xcex1-bromoacetophenone compound (7) is then condensed with appropriate thiobenzamide (2) as described before to form the diarylthiazole derivatives (8). Subsequent reduction of the ester with LAH followed by bromination with carbontetrabromide and triphenylphosphine yields the bromide (4a) which upon nucleophilic substitution produces the target product (6). Compound (6) can also be prepared through the mesylated intermediate (9), which is prepared by the reduction of compound (8) with LAH followed by mesylation with methanesulfonyl chloride.
A compound represented by the general formula (II) wherein p=2-3 can be prepared by the process as shown in Scheme 3 and Scheme 4:
Process 3 (Scheme 3): 
Compound (11) is obtained by condensation and cyclization thiobenzamide (2) and xcex1-bromoaceophenone (10) which is made by the bromination reaction as described before. By refluxing compound (11) in acetone with excess amount of NaI produces the iodoanalog (12) which on reaction with nucleophile produces product (13).
Process 4 (Scheme 4)
In order to prepare a compound represented by the general formula (11) wherein p=3, a palladium-catalyzed Cxe2x80x94C coupling reaction between the 4-(p-bromophenyl)thiazole derivatives (14) and an acetylenic reactant is employed. Catalytic hydrogenation of the coupling product (15) gives the extended three carbon side chain compounds (16) in very good yield (Scheme 4). 
Process 5 (Scheme 5) 
Primary amine sidechain compounds (18) can be prepared from the bromo compounds (4a) by the use of methenamine followed by cleavage of the resulting quaternary amine salts with ethanolic HCl (Organic Synthesis, Coll. V, 212). The secondary amine sidechain compounds (21) (Scheme 5) are prepared by acetylation of compounds (18) with trifluoroacetic anhydride to give the amide analogs (19) quantitatively. Treatment of the compound (19) with NaH in anhydrous DMF followed by alkylation with alkyl halide affords compound (20), which can be converted to the secondary amine products (21) by cleavage of the trieluoroacetyl group in a basic media. Compound (21) is transformed to target compounds (6) by treatment with base such as K2CO3 and appropriate alkyl halide.
Process 6 (Scheme 6) 
The xcex1-bromoacetophenones with the desired dialkylamino alkyl groups (23) are synthesized and coupled with substituted thiobenzamides (2) to give target compounds (Scheme 6). 4xe2x80x2-Methyl acetophenone or derivatives thereof are treated with NBS in CCl4 under refluxing condition to give the corresponding benzylbromides (22) which are subsequently treated with the requisite dialkylamines at room temperature to give the dialkylamino alkyl derivatives (23). These compounds are purified via flash chromatography, converted to the corresponding HCl salt, and brominated with Br2 to give xcex1-bromoacetophenones (24). Compounds (24) are reacted with substituted thiobenzamides (2) under refluxing EtOH or similar solvent to give the target compounds (25) as a mixture of HCl and HBr salts. These are converted to the free base and purified via flash chromatography as needed. Compounds wherein R7 is not hydrogen are further derivatized to additional targets. For example, compound (25) (R7=NH2) which is eventually treated with Ac2O to give the N-acetylamino compound (27) (R7=NHCOCH3).
Process 7 (Scheme 7) 
Following the procedure described in process 1, the desired thiobenzamide (2) is reacted with 3xe2x80x2methoxy-xcex1-bromoacetophenone in refluxing EtOH to give the thiazole (28). This compound is demethylated with BBr3 under standard condition to give the corresponding phenol (29). This is treated with a mixture of paraformaldehyde and requisite dialkylamine under refluxing EtOH to give target dialkylaminomethyl compounds (30).
Process 8 (Scheme 8)
A compound represented by the general formula (III) can be prepared by the process as shown in Scheme 8: 
On the basis of a known procedure (Adv. Heterocycl. Chem., 1982, 32, 285), p-methylbenzimidate hydrochloride (31) is prepared by bubbling hydrogen chloride gas through a cooled solution of p-tolunitrile in mixed solvents (1:1=chloroform and methanol). Treatment of benzimidate (31) with ammonia/methanol solution gives amidine hydrochloride (32) with ammonia/methanol solution gives amidine hydrochloride (32) quantitatively. The amidine (32) is then reacted with one equivalent of perchloromethylmercaptan in the presence of triethylamine at zero degree to give a cyclized product, 5-chloro-1,2,4-thiadiazole (33) as yellow solid. Coupling of 5-chloro-1,2,4-thiadiazole with substituted aryl Grigriard Reagents in dry THF provides the desired diaryl 1,2,4-thiadiazoles (34) (J. Am. Chem. Soc., 1985, 107, 2033 and organometallics, 1993, 12, 3468). Subsequent bromination followed by nucleophilic substitution as described in Preparation Process 1, affords the final product (36).
Process 9 (Scheme 9)
A compound represented by the general formula (IV) and (V) can be prepared by the following process: 
The N,Nxe2x80x2-diacylhydrazine compound (J. Chem.Soc. (C), 1970, 1397) (37) is prepared by acylation of the substituted benzhydrazide at zero degree with p-methylbenzoyl chloride. The N,Nxe2x80x2-diacylhydrazine compound (37) is heated either with thionyl chloride to produce the cyclized product, 1,3,4-oxadiazole (38a) or with Lawesson""s Reagent* to exchange the oxygen to give sulfur and then cyclize to 1,3,4-thiadiazoles (38b). The cyclized products (38a and 38b) are treated with N-bromosuccinimide to give bromomethyl compounds (39a and 39b) which are reacted with appropriate nucleophiles to afford desired products (40a) and (40b) respectively.
*Lawesson""s Reagent is (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disulfide and the use of the reagent in various processes is described by M. D. Cara and M. I. Levinson in Tetrahedron; Vol. 41: pages 5061 et seq. (1985). 
One of ordinary skill in the art will recognize variations in the sequence and variations in the appropriate reaction conditions from the analogous reactions shown or otherwise known which may be appropriately used in the processes above to make the compounds of Formulae I to XIII herein.